Is EFHC1 p.Arg372Trp (c.1114C>T) pathogenic?

EFHC1 p.Arg372Trp (c.1114C>T) is classified Conflicting classifications of pathogenicity in EFHC1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1022); Rare (popmax 0.806%, sas); Associated with myoclonic epilepsy, juvenile, susceptibility to, 1.

What condition is associated with EFHC1 p.Arg372Trp (c.1114C>T)?

EFHC1 p.Arg372Trp (c.1114C>T) is associated with myoclonic epilepsy, juvenile, susceptibility to, 1, juvenile myoclonic epilepsy, epilepsy, juvenile absence, susceptibility to, 1 (ClinVar).

How common is EFHC1 p.Arg372Trp (c.1114C>T) in the general population?

EFHC1 p.Arg372Trp (c.1114C>T) is rare (popmax 0.806%, sas) (gnomAD).

What do computational predictors say about EFHC1 p.Arg372Trp (c.1114C>T)?

AlphaMissense predicts likely benign (score 0.1022) — an in-silico prediction, not a clinical call.

EFHC1 p.Arg372Trp

c.1114C>T · rs371151471 · VCV205403

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1022 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.806%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myoclonic epilepsy, juvenile, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.1022	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -10.96	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.46, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 72 kb · p 0.035 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.806% South Asian · 734/91,074 alleles

Filtering AF 0.758% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.738%

Overall 0.049% 790/1,613,706 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.806%	124
Remaining individualsnot grpmax-eligible	0.0704%	1,421
Middle Eastern	0.0165%	6,062
African / African-American	0.008%	12,503
Admixed American	0.00333%	30,000
European (non-Finnish)	0.000254%	393,331

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EFHC1
Protein: p.Arg372Trp
Coding: c.1114C>T
MANE Select: NM_018100
dbSNP: rs371151471
Type: single nucleotide variant
Location: chr6:52465092 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 2 PDB
Residue 372: a UniProt-annotated variant site (in ejm1; no effect on protein expression; defective mitotic spindle organization; defective cytokinesis)

Full EFHC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myoclonic epilepsy, juvenile, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: juvenile myoclonic epilepsy epilepsy, juvenile absence, susceptibility to, 1

Similar variants

EFHC1 p.Arg372Gln Uncertain significance ★ ⚠ same residue
EFHC1 p.Ala445Thr Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala529Glu Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala590Pro Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala83Val Uncertain significance ★★ ⚠ same condition
EFHC1 p.Ala88Val Uncertain significance ★★ ⚠ same condition
EFHC1 p.Arg118Cys Uncertain significance ★★ ⚠ same condition
EFHC1 p.Arg151Leu Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/efhc1-p-arg372trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown